Doxepin Hydrochloride - Doxepin Hydrochloride capsule prescribing information
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of doxepin or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Doxepin is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk , PRECAUTIONS: Information for Patients and PRECAUTIONS: Pediatric Use .)
INDICATIONS AND USAGE
Doxepin Hydrochloride Capsules, USP are recommended for the treatment of:
- Psychoneurotic patients with depression and/or anxiety.
- Depression and/or anxiety associated with alcoholism (not to be taken concomitantly with alcohol).
- Depression and/or anxiety associated with organic disease (the possibility of drug interaction should be considered if the patient is receiving other drugs concomitantly).
- Psychotic depressive disorders with associated anxiety including involutional depression and manic-depressive disorders.
The target symptoms of psychoneurosis that respond particularly well to doxepin hydrochloride capsules include anxiety, tension, depression, somatic symptoms and concerns, sleep disturbances, guilt, lack of energy, fear, apprehension and worry.
Clinical experience has shown that doxepin hydrochloride capsules are safe and well tolerated even in the elderly patient. Owing to lack of clinical experience in the pediatric population, doxepin hydrochloride capsules are not recommended for use in children under 12 years of age.
DOSAGE AND ADMINISTRATION
For most patients with illness of mild to moderate severity, a starting daily dose of 75 mg is recommended. Dosage may subsequently be increased or decreased at appropriate intervals and according to individual response. The usual optimum dose range is 75 mg/day to 150 mg/day.
In more severely ill patients higher doses may be required with subsequent gradual increase to 300 mg/day if necessary. Additional therapeutic effect is rarely to be obtained by exceeding a dose of 300 mg/day.
In patients with very mild symptomatology or emotional symptoms accompanying organic disease, lower doses may suffice. Some of these patients have been controlled on doses as low as 25 to 50 mg/day.
The total daily dosage of doxepin (as the hydrochloride) may be given on a divided or once a day dosage schedule. If the once a day schedule is employed, the maximum recommended dose is 150 mg/day. This dose may be given at bedtime. The 150 mg capsule strength is intended for maintenance therapy only and is not recommended for initiation of treatment.
Antianxiety effect is apparent before the antidepressant effect. Optimal antidepressant effect may not be evident for 2 to 3 weeks.
CONTRAINDICATIONS
Doxepin hydrochloride capsules are contraindicated in individuals who have shown hypersensitivity to the drug. Possibility of cross sensitivity with other dibenzoxepines should be kept in mind.
Doxepin hydrochloride capsules are contraindicated in patients with glaucoma or a tendency to urinary retention. These disorders should be ruled out, particularly in older patients.
ADVERSE REACTIONS
NOTE: Some of the adverse reactions noted below have not been specifically reported with doxepin use. However, due to the close pharmacological similarities among the tricyclics, the reactions should be considered when prescribing doxepin.
Anticholinergic Effects
Dry mouth, blurred vision, constipation and urinary retention have been reported. If they do not subside with continued therapy or become severe, it may be necessary to reduce the dosage.
Central Nervous System Effects
Drowsiness is the most commonly noticed side effect. This tends to disappear as therapy is continued. Other infrequently reported CNS side effects are confusion, disorientation, hallucinations, numbness, paresthesias, ataxia, extrapyramidal symptoms, seizures, tardive dyskinesia and tremor.
Cardiovascular
Cardiovascular effects including hypotension, hypertension and tachycardia have been reported occasionally.
Allergic
Skin rash, edema, photosensitization and pruritus have occasionally occurred.
Hematologic
Eosinophilia has been reported in a few patients. There have been occasional reports of bone marrow depression manifesting as agranulocytosis, leukopenia, thrombocytopenia and purpura.
Gastrointestinal
Nausea, vomiting, indigestion, taste disturbances, diarrhea, anorexia and aphthous stomatitis have been reported. (See Anticholinergic Effects .)
Endocrine
Raised or lowered libido, testicular swelling, gynecomastia in males, enlargement of breasts and galactorrhea in the female, raising or lowering of blood sugar levels and syndrome of inappropriate antidiuretic hormone secretion have been reported with tricyclic administration.
Other
Dizziness, tinnitus, weight gain, sweating, chills, fatigue, weakness, flushing, jaundice, alopecia, headache, exacerbation of asthma, angle closure glaucoma, mydriasis and hyperpyrexia (in association with chlorpromazine) have been occasionally observed as adverse effects.
Withdrawal Symptoms
The possibility of development of withdrawal symptoms upon abrupt cessation of treatment after prolonged doxepin administration should be borne in mind. These are not indicative of addiction and gradual withdrawal of medication should not cause these symptoms.
Drug Interactions
Drugs Metabolized by P450 2D6
The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7% to 10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram, fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6.
Doxepin is primarily metabolized by CYP2D6 (with CYP1A2 & CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma concentration of doxepin when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with doxepin has not been systematically evaluated.
MAO Inhibitors
Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least 2 weeks prior to the cautious initiation of therapy with doxepin. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved.
Cimetidine
Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects.
Alcohol
It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional doxepin overdosage. This is especially important in patients who may use alcohol excessively.
Tolazamide
A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin (75 mg/day).
DESCRIPTION
Doxepin hydrochloride is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds. The molecular formula of the compound is C 19 H 21 NO ∙ HCl having a molecular weight of 315.84. It is a white crystalline powder freely soluble in water, in ethanol (96%), and methylene chloride. It may be represented by the following structural formula:
Chemically, doxepin hydrochloride is a dibenzoxepin derivative and is the first of a family of tricyclic psychotherapeutic agents. Specifically, it is an isomeric mixture of 1-Propanamine, 3-dibenz[ b,e ] oxepin-11 (6 H )ylidene- N,N -dimethyl-hydrochloride.
Each 10 mg, 25 mg, 50 mg, 75 mg and 100 mg doxepin capsule for oral administration contains doxepin hydrochloride, USP equivalent to 10 mg, 25 mg, 50 mg, 75 mg and 100 mg of doxepin, respectively and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch and sodium lauryl sulfate. The empty gelatin capsule shells contain gelatin, sodium lauryl sulfate and titanium dioxide. In addition, the 10 mg empty gelatin capsule shells contain iron oxide red and iron oxide yellow, the 25 mg and 50 mg empty gelatin capsule shells contain D&C Yellow 10 and FD&C Yellow 6, and the 75 mg and 100 mg empty gelatin capsule shells contain D&C Yellow 10 and FD&C Blue 1.
The imprinting ink may contain ferrosoferric oxide, potassium hydroxide, propylene glycol and shellac glaze.
CLINICAL PHARMACOLOGY
The mechanism of action of doxepin is not definitely known. It is not a central nervous system stimulant nor a monoamine oxidase inhibitor. The current hypothesis is that the clinical effects are due, at least in part, to influences on the adrenergic activity at the synapses so that deactivation of norepinephrine by reuptake into the nerve terminals is prevented. Animal studies suggest that doxepin does not appreciably antagonize the antihypertensive action of guanethidine. In animal studies anticholinergic, antiserotonin and antihistamine effects on smooth muscle have been demonstrated. At higher than usual clinical doses norepinephrine response was potentiated in animals. This effect was not demonstrated in humans.
At clinical dosages up to 150 mg per day, doxepin can be given to man concomitantly with guanethidine and related compounds without blocking the antihypertensive effect. At dosages above 150 mg per day blocking of the antihypertensive effect of these compounds has been reported.
Doxepin is virtually devoid of euphoria as a side effect. Characteristic of this type of compound, doxepin has not been demonstrated to produce the physical tolerance or psychological dependence associated with addictive compounds.
HOW SUPPLIED
Doxepin Hydrochloride Capsules, USP are available containing doxepin hydrochloride, USP equivalent to 10 mg, 25 mg, 50 mg, 75 mg or 100 mg of doxepin.
The 10 mg capsule is a hard-shell, gelatin capsule with a tan opaque cap and tan opaque body, axially printed with TARO over D10 in black ink on both the cap and the body. They are available as follows: NDC 51672-4217-1 bottles of 100 capsules
The 25 mg capsule is a hard-shell, gelatin capsule with a yellow opaque cap and white opaque body, axially printed with TARO over D25 in black ink on both the cap and the body. They are available as follows: NDC 51672-4218-1 bottles of 100 capsules
The 50 mg capsule is a hard-shell, gelatin capsule with a yellow opaque cap and yellow opaque body, axially printed with TARO over D50 in black ink on both the cap and the body. They are available as follows: NDC 51672-4219-1 bottles of 100 capsules
The 75 mg capsule is a hard-shell, gelatin capsule with a green opaque cap and green opaque body, axially printed with TARO over D75 in black ink on both the cap and the body. They are available as follows: NDC 51672-4220-1 bottles of 100 capsules
The 100 mg capsule is a hard-shell, gelatin capsule with a green opaque cap and white opaque body, axially printed with TARO over D100 in black ink on both the cap and the body. They are available as follows: NDC 51672-4221-1 bottles of 100 capsules
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Protect from light.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
